Course Of Metastatic Breast Cancer Research Articles

The prognostic role of variations in tumour markers (CEA, CA15.3) in patients with metastatic breast cancer treated with CDK4/6 inhibitors.

Tumour markers have no established role in the monitoring of the course of metastatic breast cancer during antineoplastic therapy, yet cancer antigen 15.3 (CA15.3) and carcinoembryonic antigen (CEA) are commonly used in clinical practice to aid in the early detection of progression of disease (PD). In our multicentre, prospective, real-life study, we enrolled 142 consecutive patients with advanced breast cancer receiving endocrine therapy in combination with a CDK4/6 inhibitor from January 2017 to October 2020; 75 patients had PD at the time of database closure. We measured serum marker concentrations at regular 4-month intervals together with radiological tumour response assessments and in cases of clinical suspicion of PD. Appropriate descriptive and inferential statistical methods were used to analyse serum marker level trends amongst prespecified subgroups and at specific time points (baseline, best radiologically documented tumour response and first detection of PD) in the subpopulation of patients with PD at the time of database closure. Notably, the median time from treatment initiation to best tumour response was 4.4 months. We evaluated the presence of an association between baseline CA15.3 and CEA levels and prespecified clinical characteristics but found no clinically meaningful correlation. We assessed marker level variations at the time of best radiologically documented disease response and PD: in the subgroup of patients who responded to treatment before progressing, we detected a statistically significant correlation with tumour marker variation between the time of best response and progression; this finding was not confirmed in the subgroup of patients that did not benefit from treatment. In conclusion, serum tumour marker flares can be useful in the early diagnosis of PD but should not be used as the sole factor prompting a change in treatment strategy without radiological confirmation.

Protein analysis of extracellular vesicles to monitor and predict therapeutic response in metastatic breast cancer

Molecular profiling of circulating extracellular vesicles (EVs) provides a promising noninvasive means to diagnose, monitor, and predict the course of metastatic breast cancer (MBC). However, the analysis of EV protein markers has been confounded by the presence of soluble protein counterparts in peripheral blood. Here we use a rapid, sensitive, and low-cost thermophoretic aptasensor (TAS) to profile cancer-associated protein profiles of plasma EVs without the interference of soluble proteins. We show that the EV signature (a weighted sum of eight EV protein markers) has a high accuracy (91.1 %) for discrimination of MBC, non-metastatic breast cancer (NMBC), and healthy donors (HD). For MBC patients undergoing therapies, the EV signature can accurately monitor the treatment response across the training, validation, and prospective cohorts, and serve as an independent prognostic factor for progression free survival in MBC patients. Together, this work highlights the potential clinical utility of EVs in management of MBC.

Significant impact of circulating tumour DNA mutations on survival in metastatic breast cancer patients

Mutational analysis of circulating tumour (ct) DNA holds promise as an effective tool to predict the course of metastatic breast cancer (MBC). In the present study we used targeted next generation sequencing of ctDNA to evaluate the impact of cancer driven mutations on the prognosis of MBC. The study included 59 oestrogen receptor-positive (ER+), HER2-negative MBC patients. Sequencing analysis was performed in ESR1, PIK3CA, ERBB2, PTEN, TP53, KRAS, HRAS, NRAS, and AR. At baseline, patients started receiving either chemotherapy (34%; n = 20) or cyclin-dependent kinase 4/6 inhibitor therapy in combination with endocrine therapy (CDK4/6i+ET; 66%; n = 39). Overall, 64.4% (n = 38) of the patients carried at least one pathogenic or likely-pathogenic mutation. Number of ctDNA mutations was significantly linked with worse progression free survival (PFS; p = 0.003) and overall survival (OS; p = 0.007). Furthermore, ctDNA load, defined by the number of mutant ctDNA molecules per mL plasma, significantly correlated with PFS (p < 0.001) and OS (p = 0.001). Furthermore, mutational status of ESR1 and TP53 significantly predicted PFS (p = 0.024 and p = 0.035, respectively) and OS (p < 0.001 and p = 0.035, respectively). These results emphasizes the clinical value of ctDNA mutational analysis in the management of advanced breast cancer.

Abstract PS2-26: Evaluating the pathogenicity of emerging genomic aberrations detected by circulating tumor DNA over the course of metastatic breast cancer

Abstract Introduction: Previously reported data from our group and others have demonstrated an increase in genomic complexity and number of alterations over the course of treatment in MBC. Our study aims to categorize the pathogenicity of genomic aberrations found on serial ctDNA evaluations in MBC to explore the relevance of emerging mutations. Methods: Patients with MBC and ctDNA next-generation sequencing (NGS) analysis by Guardant360 (Guardant Health, Redwood City, CA) completed from 2015 to 2019 were retrospectively identified with an IRB-approved protocol. Clinical-pathologic features and time point for progression of disease were abstracted from review of the electronic medical record. Among the 255 patients with ctDNA analysis, 85 patients had serial ctDNA analysis from baseline and at subsequent progression of disease (PD1) and 27 had repeat ctDNA analysis at next progression (PD2). Genomic alterations were classified as oncogenic, likely oncogenic, predictive oncogenic, likely benign, inconclusive, unknown significance, and synonymous based on categorization by OncoKB.org (Chakravarty et al, JCO PO 2017). Oncogenic, likely oncogenic, and predicted oncogenic were considered ‘pathogenic’ while the remainder were ‘not known pathogenic’. Two-sample t-tests for difference of means (α = 0.05) was used for analysis of changes in pathogenic proportions and mutant allele frequencies (MAF). Results: The median age was 53.8 years, 41 patients had hormone receptor positive (HR+) HER2-negative, 22 had HER2+, and 22 had triple negative (TN) MBC. The median and interquartile range (IQR) of the time of MBC diagnosis to first ctDNA collection was 10 mo (0.3-23.1 mo), from baseline ctDNA to analysis at the time of disease progression (PD1) was 6.7 mo (3.6-12.5 mo), and from PD1 to second progression (PD2) was 4.6 mo (3.1-8.5 mo). At baseline 66% of alterations were pathogenic (38.4% oncogenic, 27.6% likely oncogenic, 26.5% unknown significance). The proportion of pathogenic variants did not significantly change over time: 62% at PD1 (p=0.41) and 56% at PD2 (p=0.19). The percent of pathogenic alterations by disease subtype at baseline and PD1 was 66% and 60% in HR+ HER2-, 73% and 57% in HER2+, and 62% and 71% in TN. 57% and 70% of patients had a new pathogenic alteration at PD1 and PD2, respectively. The most frequently detected new pathogenic alterations at the time of disease progression were TP53, PIK3CA, ESR1, FGFR1, and MYC, which occurred in 28%, 18%, 15%, 12%, and 11% of patients, respectively. Among genes that were altered in at least 10% of patients, the aberrations were very likely to be pathogenic (&amp;gt;75% of alterations pathogenic) for TP53, PIK3CA, ESR1, MYC, BRAF, FGFR1, often pathogenic (50-75% of alterations pathogenic) for NF1, KIT, GATA3, ERBB2, EGFR, CCNE1, PDGFRA, and often not known pathogenic (&amp;lt;50% of alterations pathogenic) for MET, AR, ARID1A, and BRCA2. When comparing the mean MAF of pathogenic and not known pathogenic alterations, paired by gene, the MAF was not significantly different for pathogenic alterations except for GATA3 (p=0.03). Conclusion: The continued emergence of pathogenic mutations at times of progression without a corresponding increase in the proportion of pathogenic variants suggests that new pathogenic mutations may arise as a result of increased tumor genomic instability over time, although these findings require confirmation in larger datasets. The large proportion of patients who present with new pathogenic variants at disease progression supports the utility of ctDNA to track tumor evolution. Additionally, this study highlights the importance of considering the pathogenicity of genomic alterations, as over one-third of aberrations in MBC were not known to be pathogenic. Citation Format: Ami N Shah, Andrew A Davis, Saya Jacob, Lorenzo Gerratana, Brian Finkelman, Shruti Chandra, Neelima Katam, Firas Wehbe, Jeeven Srivastava, Ashwin Sunderraj, Qiang Zhang, Leonidas Platanias, Amir Behdad, William Gradishar, Massimo Cristofanilli. Evaluating the pathogenicity of emerging genomic aberrations detected by circulating tumor DNA over the course of metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-26.

Systematic review and meta-analysis of breast cancer brain metastasis and primary tumor receptor expression discordance.

BackgroundChange in hormone receptor (estrogen [ER] and progesterone [PR]) and/or human epidermal growth factor receptor type 2 (HER2) status during the evolutionary course of metastatic breast cancer and the effect of tumor classification subtype switching remain understudied and underappreciated in brain metastasis patients.MethodsUsing preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, a systematic review of series published prior to April 2020 obtained from the Medline database of biopsied or resected breast cancer brain metastasis (BCBM) was performed. Weighted random effects models were used to calculate pooled estimates.Results15 full-text articles were included with receptor expression analyses on 1373 patients who underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. Primary tumor receptor expression immunophenotypes were 45.0% ER+, 41.0% ER−, 31.0% PR+, 51.0% PR−, 35% HER2+, and 47.0% HER2−. Corresponding BCBM immunophenotypes were 19.0% ER+, 31.0% ER−, 13.0% PR+, 40.0% PR−, 21.0% HER2+, and 26.0% HER2−. On primary/BCBM comparison, 540 patients (42.6%) exhibited discordance in any receptor with 17.0% (95% CI: 13.0%–23.0%) discordant on ER, 23.0% (95% CI: 18.0%–30.0%) discordant on PR, and 12.0% (95% CI: 8.0%–16.0%) discordant on HER2 status. The most common receptor conversions found in BCBM were ER loss 11.0% (95% CI: 8.0%–16.0%), PR loss 15.0% (95% CI: 11.0%–21.0%), and HER2 gain 9.0% (95% CI: 7.0%–11.0%).ConclusionsBCBM exhibits significant receptor expression discordance in comparison to primary tumors in approximately 40% of patients. Classification patterns need to be analyzed to determine factors predictive of BCBM/primary tumor discordance. Overall, tumor subtype switching and its effect on clinical management remains underappreciated.

Frequent Molecular Subtype Switching and Gene Expression Alterations in Lung and Pleural Metastasis From Luminal A-Type Breast Cancer.

PURPOSEConversion of tumor subtype frequently occurs in the course of metastatic breast cancer but is a poorly understood phenomenon. This study aims to compare molecular subtypes with subsequent lung or pleural metastasis.PATIENTS AND METHODSIn a cohort of 57 patients with breast cancer and lung or pleural metastasis (BCLPM), we investigated paired primary and metastatic tissues for differential gene expression of 269 breast cancer genes. The PAM50 classifier was applied to identify intrinsic subtypes, and differential gene expression and cluster analysis were used to further characterize subtypes and tumors with subtype conversion.RESULTSIn primary breast cancer, the most frequent molecular subtype was luminal A (lumA; 49.1%); it was luminal B (lumB) in BCLPM (38.6%). Subtype conversion occurred predominantly in lumA breast cancers compared with other molecular subtypes (57.1% v 27.6%). In lumA cancers, 62 genes were identified with differential expression in metastatic versus primary disease, compared with only 10 differentially expressed genes in lumB, human epidermal growth factor receptor 2 (HER2)–enriched, and basal subtypes combined. Gene expression changes in lumA cancers affected not only the repression of the estrogen receptor pathway and cell cycle–related genes but also the WNT pathway, proteinases (MME, MMP11), and motility-associated cytoskeletal proteins (CK5, CK14, CK17). Subtype-switched lumA cancers were further characterized by cell proliferation and cell cycle checkpoint gene upregulation and dysregulation of the p53 pathway. This involved 83 notable gene expression changes.CONCLUSIONOur results indicate that gene expression changes and subsequent subtype conversion occur on a large scale in metastatic luminal A–type breast cancer compared with other molecular subtypes. This underlines the significance of molecular changes in metastatic disease, especially in tumors of initially low aggressive potential.

Hallmarks of Bone Metastasis.

Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient's quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.

Circulating tumor cell count and thrombosis in metastatic breast cancer

Background Circulating tumor cell (CTC) count is a major prognostic factor in metastatic breast cancer (MBC) and has been reported to be associated with thrombosis in short-term studies on MBC patients. Objective To assess whether CTC detection (CellSearch® ) before first-line chemotherapy impacts the risk of thrombosis throughout the course of MBC. Patients/Methods Among patients included before first-line chemotherapy for MBC in the prospective IC2006-04 CTC detection study (NCT00898014), the electronic medical files of those patients treated at Institut Curie (Paris, France) were searched in silico and manually checked for incident venous or arterial thrombotic events (TE) in the course of MBC. Univariate and multivariate analyses were performed using Cox and Fine-Gray models, adjusted for age and Khorana score. Results/Conclusions With a median follow-up of 64months (25-81months), among the 142 patients included, 34 (24%) experienced a TE (incidence rate, 8 TE/100 patient-years). The TE incidence rate was 13 TE/100 patient-years for the 80 patients with ≥1 CTC/7.5mL of blood before initiating first-line chemotherapy, vs. only 4 TE/100 patient-years for the 62 CTC-negative patients. Fine-Gray multivariate analysis (with death as competing event) included age, Khorana score and baseline lactate dehydrogenase and CTC levels: detectable CTC was the only factor significantly associated with an increased risk of TE (sub-distribution hazard ratio[SHR] for patients with [1-4] CTC=3.1, 95% CI [1.1; 8.6], SHR for patients with ≥5 CTC=1.4, 95% CI [0.5; 4.6]). This study shows that CTC detection before starting first-line chemotherapy is an independent risk factor for TE in MBC patients.

Abstract P2-02-08: Initial circulating tumor cell count and venous thrombosis-free interval in the course of metastatic breast cancer

Abstract Background: Circulating tumor cells (CTC) count is a major prognostic factor in metastatic breast cancer. It has been also reported to be associated with venous thrombosis in short-term studies on advanced metastatic breast cancer patients. Methods: We assessed whether an early CTC detection (CellSearch®), before the start of the first line chemotherapy, impacts Thrombosis-Free Interval during the whole course of metastatic breast cancer. Electronic medical files of all patients included in the large prospective IC 2006-04 CTC detection study (NCT00898014, Pierga et al, Ann Oncol 2012) and treated at Institut Curie (Paris, France) were manually and automatically searched for thrombosis events in the course of their metastatic breast cancer. Superficial venous thromboses were not taken into account.Thrombosis-Free Interval (TFI) was defined as the first event occuring between venous or arterial thrombosis. Results: In the 142 patients studied, with a median follow-up of 64 months [25-81 months], venous (deep venous thrombosis, pulmonary embolism, catheter thrombosis and portal vein thrombosis) and arterial thrombosis occurred in 21.8% and 4.2% of patients, respectively. Twenty-four (30%) of the 80 patients with ≥1 CTC/7.5ml of blood before the start of first line chemotherapy experienced at least one thrombotic events in the course of their disease, while only 10 (16%) of the 62 CTC-negative patients experienced a similar event (p=0.06). Baseline positive CTC was associated with a higher risk of experiencing a venous or arterial thrombosis (TFI: HR=2.6 [1.2-5.5], p=0.009). The median TFI was 64 months in CTC-positive patients and not reached in CTC-negative patients. Among the other patients characteristics tested at baseline, Performance Status (PS=1 vs PS=0: HR=0.85 [0.4-1.9], p=NS; PS=2 or 3 vs PS=0: HR=3.7 [1.5-8.7], p=0.003) and LDH levels at baseline (LDH&amp;gt;UNL vs LDH&amp;lt;UNL HR=2.4 [1.2-4.9], p=0.012) were also associated with TFI. Conclusions: Metastatic breast cancer patients with ≥1 CTC before the start of chemotherapy are at higher risk of venous thrombosis; the clinical relevance of thrombo-prophylaxis should be investigated in this population. Citation Format: Beinse G, Berger F, Cottu PH, Dujaric M-E, Kriegel I, Guilhaume M-N, Dieras V, Beuzeboc P, Pierga J-Y, Bidard F-C. Initial circulating tumor cell count and venous thrombosis-free interval in the course of metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-08.

Differentiation of overall survival by breast cancer tumor subtype following stereotactic radiosurgery for brain metastasis.

e11584 Background: Brain metastases occur late in the course of metastatic breast cancer and the median survival from time of brain metastases has historically been ~4 months. Stereotactic radiosur...

Cerebral metastases in metastatic breast cancer: disease-specific risk factors and survival

BackgroundSurvival of patients suffering from cerebral metastases (CM) is limited. Identification of patients with a high risk for CM is warranted to adjust follow-up care and to evaluate preventive strategies. Patients and methodsExploratory analysis of disease-specific parameter in patients with metastatic breast cancer (MBC) treated between 1998 and 2008 using cumulative incidences and Fine and Grays’ multivariable regression analyses. ResultsAfter a median follow-up of 4.0 years, 66 patients (10.5%) developed CM. The estimated probability for CM was 5%, 12% and 15% at 1, 5 and 10 years; in contrast, the probability of death without CM was 21%, 61% and 76%, respectively. A small tumor size, ER status, ductal histology, lung and lymph node metastases, human epidermal growth factor receptor 2 positive (HER2+) tumors, younger age and M0 were associated with CM in univariate analyses, the latter three being risk factors in the multivariable model. Survival was shortened in patient developing CM (24.0 months) compared with patients with no CM (33.6 months) in the course of MBC. ConclusionYoung patients, primary with non-metastatic disease and HER2+ tumors, have a high risk to develop CM in MBC. Survival of patients developing CM in the course of MBC is impaired compared with patients without CM.

Bone marrow carcinosis in breast cancer: Clinical presentation, treatment, and prognosis—A single institution review of 22 cases.

e11514 Background: Development of bone marrow carcinosis (BMC) is a rare event in the course of metastatic breast cancer. There are little data regarding its clinical presentation, prognosis, optimal treatment, and associated complications. We analyzed 22 breast cancer patients (pts) with proven BMC diagnosed at our institution between 1995 and 2009. Methods: The data were gathered from pts' charts after approval of the institutional review board. In view of the limited number of cases, a purely descriptive analysis was performed. BMC was assumed in case of histologic or cytologic evidence of diffuse bone marrow infiltration by carcinomatous cells (17 pts) or in case of appearance of erythroblasts in the peripheral blood smear in pts with otherwise unexplained cytopenia (5 pts). Results: All pts presented with osseous metastases at the time of diagnosis of BMC. Anemia was the most prominent hematologic sign present in 77% followed by thrombocytopenia. Cytotoxic treatment was offered to 95% of pts. The majority showed an improvement of their cytopenias following treatment (10 out of 14 anemic pts, 6 out of 9 thrombocytopenic pts, all 4 leukopenic pts). The complication rate was acceptable with only 5 grade 3 or 4 events related to cytopenias (febrile neutropenia, bleeding). Estimated median overall survival from the date of BMC diagnosis was 19 months. After 4 years, 20% of the pts were still alive. Conclusions: We conclude that bone marrow carcinosis in breast cancer has to be considered in particular in pts with bone metastases and otherwise unexplained cytopenia. The peripheral blood smear can serve as a simple diagnostic tool. Cytopenia should not prevent from treating these pts even with aggressive combination regimens, as improvement of marrow function can be achieved in the majority of pts and long lasting survival is possible. No significant financial relationships to disclose.

Level of psychological distress in patients with metastatic breast cancer is largely defined by predisposition

9579 Background: Psychological distress diminishes quality of life in patients with incurable cancer. Although studies state that distress naturally progresses towards the end of life, it could also result from a patient’s individual susceptibility. Therefore, distress was studied in breast cancer patients who participated in the Dutch Bone Metastasis Study. Methods: From March 1996 to September 1998, 1157 patients with painful bone metastases from solid tumors were randomized between single or multiple fraction radiotherapy. During follow-up, patients filled out 13 weekly and thereafter monthly questionnaires to a maximum of 2 years or until death. The Rotterdam Symptom Checklist psychological subscale of 7 items was used. The minimal sum score is 7, a sum score of 28 indicates maximum psychological distress. A sum score above 17 is valued as needing further psychological assessment. At randomization, 3 risk groups for distress were identified: low (score 7–11), intermediate (score 12–16), and high (score 17–28). Distress was analyzed as a function of remaining lifetime in patients who died within the study period. Age, time since primary diagnosis, performance score, pain score and presence of visceral metastases were studied as baseline risk factors for distress. Results: At randomization, 448 women with breast cancer were identified; 37% was low, 30% intermediate and 33% high risk with regard to distress. Median overall survival was similar in all risk groups (17 months, p= 0.8), with 66% of patients dying within the study period. In the high risk group, mean scoring was constant towards the end of life (table). Both low and intermediate risk groups showed a small increase towards death, but stayed below threshold level. No significant risk factors for distress were found. Conclusions: Predisposition rather than the course of metastatic breast cancer seems to define patients at risk for psychological distress. Interventions should be provided to patients identified as high risk early on in the disease. Distress towards death using the Rotterdam Symptom Checklist psychological subscale. Psychological distress per questionnaire returned towards death#, mean score (SD) Risk groups* Q16 Q12 Q9 Q6 Q3 Q1 Low 9 (2) 9 (2) 9 (2) 9 (3) 10 (4) 11 (4) Intermediate 13 (4) 14 (4) 13 (4) 14 (4) 14 (4) 15 (5) High 18 (5) 17 (5) 17 (5) 18 (5) 17 (5) 18 (5) * sum scoring at randomization into 3 risk groups low risk= 7–11, intermediate risk= 12–16, high risk= 17–28. # refers to the time until death, e.g. Q9 is the ninth questionnaire before death, Q1 is the last questionnaire before death. No significant financial relationships to disclose.

Do Serum Angiogenic Growth Factors Provide Additional Information to That of Conventional Markers in Monitoring the Course of Metastatic Breast Cancer?

Objective:Our work evaluated the potential role of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) serum levels with respect to that of conventional serum tumour markers, CEA and CA 15-3, in monitoring the course of metastatic breast cancer in 56 female patients treated with cytotoxic chemotherapy. Methods: VEGF and bFGF concentrations were determined using a quantitative sandwich enzyme immunoassay technique. The positive predictive value (PPV) of each marker and of marker combinations for different types of clinical response was calculated. Results: The highest PPV for overall disease control was shown by bFGF (70%), which also showed the highest PPV for both partial response (36.4%) and stable disease (63.2%). CEA showed the highest predictive value for progression (69.2%). A combined increase in CEA and bFGF or VEGF was associated with disease progression in all patients. Conclusions:Information provided by angiogenic factor levels seems to be independent of and is possibly complementary to that provided by conventional serum markers. bFGF showed the maximum predictive value for disease control and provided additional information to that obtained from CEA or CA 15-3 evaluation. It could therefore be a promising candidate for monitoring response to chemotherapy in advanced breast cancer.

The course of serum HER-2/neu levels as an independent prognostic factor for survival in metastatic breast cancer

The purpose of this study was to determine the impact of serum HER-2/neu level dynamics during the course of disease and treatment on the prognosis of patients with metastatic breast cancer. Two thousand and thirty-eight serum samples collected sequentially after disease relapse in 286 patients with metastatic breast cancer were measured by Bayer Immuno 1 trade mark assay retrospectively for serum HER-2/neu (cut-off level 15 ng/ml). One hundred and five patients (37%) presented with serum HER-2/neu continuously </=15 ng/ml after disease recurrence, 71 (25%) had continuously elevated levels and 110 patients (38%) had both non-elevated and elevated values in the course of metastatic breast cancer. Patients with continuously elevated serum HER-2/neu levels had a significantly poorer survival after disease recurrence compared to patients with continuously or temporarily non-elevated serum HER-2/neu values (log-rank test: p<0.001). Including the number of palliative antitumor therapies and therapy response in Cox regression analysis, serum HER-2/neu dynamics revealed to be an independent prognostic factor for survival. In conclusion, 63% of 286 patients with metastatic breast cancer demonstrated either continuously or temporarily elevated serum HER-2/neu levels. Decrease of elevated serum HER-2/neu to levels </=15 ng/ml and levels continuously </=15 ng/ml during the course of disease correlated significantly with longer survival.

Maximizing the response to Herceptin therapy through optimal use and patient selection.

The aggressiveness of human epidermal growth factor receptor-2 (HER2)-positive breast cancer and the poor prognosis of women with this disease demand the availability of accurate and reliable tests for HER2 status and the optimization of HER2-targeted therapy. The distinctive clinical pattern of HER2-positive breast cancer underlines the importance of testing for HER2 status and efforts are ongoing to validate the two major methods in use-immunohistochemistry (IHC), which measures cell membrane HER2 expression, and fluorescence in situ hybridization (FISH), which measures gene copy number. Clinical trial results demonstrate that there is an association between strong HER2 overexpression (IHC 3+) and optimal response to therapy with the novel recombinant HER2 antibody Herceptin. High levels of concordance between IHC 3+ and FISH-positive status have been observed, and response to treatment with Herceptin is similar for patients whose breast cancers are IHC 3+ and those who are FISH-positive. Observations to date have led to the formulation of an algorithm for HER2 status determination and Herceptin use which recommends that: (i) the HER2 status of all women with breast cancer be determined at presentation, (ii) all IHC 3+ and FISH-positive patients with metastatic disease should receive Herceptin, (iii) Herceptin should be used early in the course of metastatic breast cancer and preferably first line, and (iv) Herceptin therapy should be continued until disease progression.

THE CLINICAL RELEVANCE OF METASTATIC PATTERN IN BREAST-CANCER - THE HETEROGENEITY OF METASTATIC DISEASE

Patients with metastatic breast cancer are considered as a homogeneous group because of the relative rarity of data relating to specific organ metastases. In this study, the clinical course of metastatic breast cancer was documented for 278 female patients registered from 1978 through 1988 at the Clinic for Radiotherapy of the University of Wurzburg. We analysed these 278 patients with metastatic disease to work out the clinical significance of specific organ metastases (SOM). A comparison of the six most frequent specific organ metastatases (SOM), i.e., bone, lung, CNS, liver, lymph node and skin metastases, is presented. Our findings indicate, that the group of patients with metastatic disease is heterogenous relating to age at time of metastatic disease, to metastatic-free intervall and to the influence of specific organ metastases on survival. The heterogeneity in the group of patients with distant metastatic disease has to be taken in consideration, when the results of chemotherapy are reported.

Prognostic factors for the course of metastatic breast cancer : K.W.Brunner, M.F.Fey, Institute for Medical Oncology, Inselspital, CH-3010 Bern

Prognostic factors for the course of metastatic breast cancer : K.W.Brunner, M.F.Fey, Institute for Medical Oncology, Inselspital, CH-3010 Bern